DESCRIPTION: Cardiovascular disease (CVD) is the leading cause of death worldwide. Despite the major technological advances in stent therapy over the past two decades, restenosis and thrombosis (primarily late and very late) remain principal factors contributing to stent-associated morbidity and mortality rates. To date, stent therapies are non-selective, affecting vascular smooth muscle cells and endothelial cells alike and exacting unfavorable trade-offs. Drug-eluting stents (DES) effectively suppress neointimal growth, but at the expense of poor stent strut coverage with incompetent endothelium. This inability to deliver cell-selective therapy has hindered progress in percutaneous interventions. In response, we have developed an innovative microRNA (miRNA)- based, cell-selective therapy that achieved striking results in an established normal rat model of balloon angioplasty. This novel therapy selectively inhibited neointimal hyperplasia and inflammation while simultaneously promoting vessel reendothelialization, reducing hypercoagulability and restoring the endothelium-dependent vasodilatory response to levels indistinguishable from uninjured control. To translate this therapeutic strategy to a clinical setting, and better reflect the condition of patients that undero interventional procedures, we aim to test the efficacy of our strategy in a rabbit model of established atherosclerosis. In three specific aims, we will evaluate the ability of this miRNA-based, cell-selective therapy to (1) inhibit atherogenesis; (2) promote atheroregression; and (3) inhibit in-stent restenosis and restore endothelial-strut coverage when compared against DES. These studies have tremendous therapeutic implications, and their successful completion will advance the development of cell-selective therapies and significantly impact the clinical practice of cardiovascular intervention to improve the life expectancy of CVD patients.